title: Control of pathogenicity and disease specificity of a T-lymphomagenic gammaretrovirus by E-box motifs but not by an overlapping glucocorticoid response element.
abstract: Although transcription factors of the basic helix-loop-helix family have been shown to regulate enhancers of lymphomagenic gammaretroviruses through E-box motifs, the overlap of an E-box motif (Egre) with the glucocorticoid response element (GRE) has obscured their function in vivo. We report here that Egre, but not the GRE, affects disease induction by the murine T-lymphomagenic SL3-3 virus. Mutating all three copies of Egre prolonged the tumor latency period from 60 to 109 days. Further mutating an E-box motif (Ea/s) outside the enhancer prolonged the latency period to 180 days, suggesting that Ea/s works as a backup site for Egre. While wild-type SL3-3 and GRE and Ea/s mutants exclusively induced T-cell lymphomas with wild-type latencies mainly of the CD4(+) CD8(-) phenotype, Egre as well as the Egre and Ea/s mutants induced B-cell lymphomas and myeloid leukemia in addition to T-cell lymphomas. T-cell lymphomas induced by the two Egre mutants had the same phenotype as those induced by wild-type SL3-3, indicating the incomplete disruption of T-cell lymphomagenesis, which is in contrast to previous findings for a Runx site mutant of SL3-3. Mutating the Egre site or Egre and Ea/s triggered several tumor phenotype-associated secondary enhancer changes encompassing neighboring sites, none of which led to the regeneration of an E-box motif. Taken together, our results demonstrate a role for the E-box but not the GRE in T lymphomagenesis by SL3-3, unveil an inherent broader disease specificity of the virus, and strengthen the notion of selection for more potent enhancer variants of mutated viruses during tumor development.
authors.affiliation: Department of Molecular Biology, University of Aarhus, C. F. Møllers Alle, bldg. 130, DK-8000 Aarhus, Denmark.
authors.forename: Ditte
authors.initials: D
authors.lastname: Ejegod
authors.forename: Karina Dalsgaard
authors.initials: KD
authors.lastname: Sørensen
authors.forename: Ilona
authors.initials: I
authors.lastname: Mossbrugger
authors.forename: Leticia
authors.initials: L
authors.lastname: Quintanilla-Martinez
authors.forename: Jörg
authors.initials: J
authors.lastname: Schmidt
authors.forename: Finn Skou
authors.initials: FS
authors.lastname: Pedersen
mesh_terms: D000818:Animals; D004279:DNA, Viral / Q000235:genetics; D017988:Gammaretrovirus / Q000235:genetics* / Q000472:pathogenicity*; D015994:Incidence; D008223:Lymphoma / Q000821:virology*; D051379:Mice; D009154:Mutation; D020218:Response Elements
chemical_list: D004279:DNA, Viral